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PED3011 Toxicology > Liver Toxicity > Flashcards

Liver Toxicity Flashcards

1
Q

What is toxicity

A

Undesirable effect that may lead to cell death

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2
Q

What is the difference between apoptosis and necrosis

A

Necrosis: unplanned cell death
Apoptosis: programmed cel death

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3
Q

What are the key signs of apoptosis

A

Organelle swelling
ATP levels fall
Loss of plasma membrane integrity
Release of intracellular contents and digestion by lysosomal enzymes
Local inflammation

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4
Q

What are the key signs of apoptosis

A

Signal dependent
ATP levels remain high
No release of cell contents
Digestion by caspase enzymes = no inflammation

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5
Q

What are examples of direct and indirect toxicity

A

Direct: heat, oxygen deprivation and chemical damage
Indirect: pro-toxin that requires activation

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6
Q

Why is the liver subjected to the toxic action of many xenobiotics?

A

Liver is the first organ to see xenobiotics after gut absorption
Liver expresses high levels of enzymes to metabolise xenobiotics

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7
Q

What region of the liver activates paracetamol, CCl4, bromobenzene and allyl alcohol

A

Paracetamol, CCl4, bromobenze: centrilobular
Allyl alcohol: periportal

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8
Q

Describe paracetamol metabolism at therapeutic doses

A

Phase 2 metabolism: 50/50 glucurondiation and sulfation

Small proportion via CYP3A4

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9
Q

How does CYP3A4 metabolise paracetamol

A

N-hydroxylation
Loses H20 and rearrangement to NAPQI

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10
Q

Describe paracetamol metabolism at supratherapeutic doses

A

Pathways oversaturated so higher proportion of paracetamol metabolised to NAPQI

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11
Q

Describe the structure of the liver

A

Biggest internal organ
2 major lobes
2 sets of incoming blood hepatic and portal
Major blood supply is portal

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12
Q

What are the 2 distinctive vessel structures in the liver

A

Central vein
Portal tract

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13
Q

What other vessel structures are in the liver

A

Bile duct
Portal venue = from gut
Portal arteriole = branch of artery

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14
Q

What are the 2 conceptual units of the liver

A

Lobule
Acini

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15
Q

Describe the structure of a lobule

A

Make up lobes
Hexagonal in shape
Rows of hepatocytes that radiate from a central point

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16
Q

Describe how hepatocytes are laid out in a lobule

A

Close contact with sinusoids
Adjacent to canaliculi

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17
Q

How are arteries and veins layed out in hepatocytes

A

Branches of hepatic artery, portal vein and bile duct around perimeter
Cluster at corners of lobule forming portal triad
Central vein at mid-point of lobule

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18
Q

Describe the blood flow in a lobule

A

Out of the sinusoids into central vein and transported out of liver

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19
Q

Describe the expression of CYP2E1 in the lobule

A

Mainly around central veins and portal vein
More intense brown staining in those areas

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20
Q

Describe the structure of the acini

A

Irregular shaped mass of hepatocytes
Small portal tract at the centre
Terminal hepatic venules at periphery

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21
Q

Describe how the zones are layed out in the acini

A

1: surrounds portal tract (peri portal)
2: mid
3: surrounds hepatic venule (pericentral)

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22
Q

Describe the blood flow in the acinus

A

Portal tract through the zones to the venule
Zone 1 (high O2) -> Zone 3 (low O2)

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23
Q

What is the function of hepatocytes

A

Most functions of the liver
High metabolic activity

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24
Q

Describe the function of Kupffer cells

A

Sit in sinusoid and allow blood to flow
Resident liver macrophages

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25
Q

Describe the function of endothelial cells

A

Fenestrated - have holes in them to allow things to flow through
Surround Kupffer cells

26
Q

Describe the function of hepatic Stella te cells

A

Sit between hepatocytes and endothelial cells
Store vitamin A
Produce myofibroblasts in injury

27
Q

Describe carbohydrate metabolism in the liver in the fed state

A

Glucose -> glycogen
Glucose -> pyruvate -> Ac-CoA -> fatty acids, TGs

Not much glycogen -> glucose
Not much pyruvate -> lactate

28
Q

Describe carbohydrate metabolism in the liver in the starvation state

A

Glycogen -> glucose
Amino acids -> pyruvate -> glucose

Main function is to reform glucose for survival

29
Q

Describe carbohydrate metabolism in the liver in the CORI cycle

A

Muscle: Glucose -> pyruvate (produces small amount of ATP)
Pyruvate -> lactate

Liver: lactate -> pyruvate -> glucose
Glycogen -> glucose
Gluconeogenesis

30
Q

What is the role of the liver in protein metabolism

A

Non-essential amino acid synthesis
Amino acid re-amination
Expression of serum transport proteins
Clotting factors

31
Q

How does the liver get rid of excess ammonia

A

Convert it to urea

32
Q

What is the role of the liver in lipid metabolism

A

Fatty acid synthesis
Triglyceride synthesis
Cholesterol synthesis
Bile acid synthesis
Lipid oxidation

33
Q

Describe the breakdown of erythrocytes

A

Spleen: RBC -> haem -> bilirubin
Liver: glucuronidates bilirubin and excretes into bile

34
Q

What causes jaundice

A

Build up of bilirubin in blood
Suggests liver damage/failure

35
Q

What is the function of Kupffer cells

A

Phagocytosis of particulates/bacteria
Prevent contents of GI becoming systemic

36
Q

Describe liver failure

A

Hepatocytes are damaged
Localised to lobular region or acini

37
Q

What biochemical markers are used as evidence of current damage

A

ALT
AST
Y-GT
ALP

38
Q

What biochemical markers are used as evidence of liver function

A

Bilirubin
Ammonia and urea
Pro-thrombin time

39
Q

When would a liver biopsy be performed

A

When there is grade chronic liver damage

40
Q

What are the pros and cons of a liver biopsy

A

+ : see liver structure and help diagnose causesof disease
- : only see a fraction of liver and risks associated w procedure

41
Q

What are the different stages of liver damage

A

1: steatosis
2: necrosis
3: fibrosis
4: cirrhosis
5: primary liver cell cancer

42
Q

How does GSH protect cells

A

GSH nucleophillic
2e- in thiol group attract electrophillic sulfhydryl reactive agents and conjugates with them

Reduce oxidised thiols

43
Q

When does toxicity to paracetamol occur

A

When GSH is depleted by NAPQI by 80%

44
Q

What are the antidotes to paracetamol toxicity

A

N acetyl cysteine or methionine

45
Q

Why is methionine not as routinely used in paracetamol overdose

A

Affects folic acid levels
Long term effect on the heart

46
Q

How can GSH reduce H2O2

A

GSH peroxidase acts on H2O2 and converts it to H20

GSH reductase converts oxidised GSH to GSH

47
Q

Why is GSH reductase important

A

Oxidised GSH (GSSG) can’t protect thiols
Need to be reduced back to GSH

48
Q

Whats a better animal model of paracetamol toxicity

A

Mouse not rat
Rat have a greater basal and active capacity for hepatic stress response

49
Q

Describe CCl4

A

Toxin that produces cell death in hepatocytes

50
Q

Describe the activation hypothesis of CCl4

A

Reduced by CYP450 (addition of e-) = homolytic fission of covalent bond
= chloride ion + trichloromethyl radical

51
Q

In what area is necrosis due to CCl4 seen in

A

Centrilobular region
Activated by CYP2E1

52
Q

What are the biochemical effects of CCl4 intoxication on the ER

A

ER degranulation and swelling within2 hours
ER enzyme inactivation

53
Q

Is CCL4 mutagenic

A

Not mutagenic
Weak carcinogen

54
Q

What is the biochemical effects of CCl4 intoxication on the mitochondria

A

Intact for several hours then swell
Uncontrolled respiration
Depleted ATP
Inactivated enzymes

55
Q

Describe how CCl4 forms a peroxytrimethyl radical

A

CYP450s reduce CCl4 = trimethyl radical (CCl3)
CCl3 + O2 dissolved in membrane = peroxytrimethyl radical (CCl3O2)

56
Q

What happens after CCl3O2 is formed from CCL4

A

Radical extracts H+ and e- from lipid to from lipid radical
Lipid radical reacts w O2 = peroxylipid radical (LOO)
LOO + another lipid = lipid hydroperoxide and new lipid radical

Affects membrane fluidity as more radicals will form as long as O2 is present

57
Q

What can prevent lipid peroxidation and what is the mechanism

A

Vitamin E
Inhibits process to a some extent by reacting with radicals to from stable radical

58
Q

What is an allyl alcohol

A

3 carbon molecule that has an alcohol

59
Q

Describe the metabolism of allyl alcohols

A

Alcohol ——————> aldehyde ————————> acid
Alcohol dehydrogenase Acetaldehyde dehydrogenase

60
Q

How does the body prevent aldehyde toxicity

A

ALDH is very fast to keep low levels of aldehydes

61
Q

How are aldehydes reactive

A

O=C-H is reactive to amines and thiols e.g proteins and biogenic amines

Depleted GSH from cells

PED3011 Toxicology (11 decks)

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